The protease-activated receptor 1 (PAR1) is a thrombin receptor which belongs to the class of G protein-coupled receptors (GCPR). PAR1 is expressed in various tissues, e.g., endothelial cells, smooth muscles cells, fibroblasts, neurons and human platelets. It is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. Thrombin-mediated stimulation of platelet aggregation via PAR1 is an important step in clot formation and wound healing in blood vessels. Thrombin activates PAR1 by proteolytic removal of a portion of the extracellular N-terminal domain of PAR1 and exposing a new PAR1 N-terminus. The first few amino acids (SFLLRN; SEQ ID NO:37) of the new PAR1 N-terminus then act as a tethered ligand that binds to another part of the receptor to initiate signaling by an associated G-protein. PAR1 can also be activated by other serine proteases involved in blood clotting.
Modulation of PAR1-mediated signaling activities has several therapeutic applications. Inhibition of PAR1 is helpful for treating thrombotic and vascular proliferative disorders as well as for inhibiting progression of cancers. See, for example, Darmoul, et al., Mol Cancer Res (2004) 2(9):514-22 and Salah, et al, Mol Cancer Res (2007) 5(3):229-40. A PAR1 inhibitor, including an antagonist antibody or antigen binding molecule, has utility in the treatment of numerous disease conditions mediated by PAR1 intracellular signaling. For example, a PAR1 inhibitor, including an antagonist antibody or antigen binding molecule, finds use in preventing or inhibiting chronic intestinal inflammatory disorders, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and ulcerative colitis; and fibrotic disorders, including liver fibrosis and lung fibrosis. See, for example, Vergnolle, et al., J Clin Invest (2004) 114(10): 1444; Yoshida, et al, Aliment Pharmacol Ther (2006) 24(Suppl 4):249; Mercer, et al., Ann NY Acad Sci (2007) 1096:86-88; Sokolova and Reiser, Pharmacol Ther (2007) PMID: 17532472. A PAR1 inhibitor, including an antagonist antibody or antigen binding molecule, also finds use in preventing or inhibiting ischemia-reperfusion injury, including myocardial, renal, cerebral and intestinal ischemia-reperfusion injury. See, for example, Strande, et al., Basic Res. Cardiol (2007) 102(4):350-8; Sevastos, et al., Blood (2007) 109(2):577-583; Junge, et al., Proc Natl Acad Sci USA. (2003) 100(22):13019-24 and Tsuboi, et al., Am J Physiol Gastrointest Liver Physiol (2007) 292(2):G678-83. Inhibiting PAR1 intracellular signaling can also be used to inhibit herpes simple virus (HSV1 and HSV2) infection of cells. See, Sutherland, et al., J Thromb Haemost (2007) 5(5):1055-61.